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Description of key information

Key, report number 90500D/UCB 317/SE, skin irritation (rabbit):

not irritating

Key, report number 90499D/UCB 318/SE, eye irritation (rabbit):

severe eye damage

Key, report number UCB 314/89684 and 378/2, respiratory irritation (rat):

respiratory irritation

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06 Mar - 09 Mar 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPP 81-5 (Acute Dermal Irritation)
Version / remarks:
adopted in 1984
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
not specified
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: A. Smith, Surrey, UK
- Age at study initiation: 10 - 13 weeks
- Weight at study initiation: 2.3 - 3.0 kg
- Housing: Animals were individually housed in metal cages with perforated floors.
- Diet: SDS standard rabbits diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: rabbits were acclimated to the laboratory environment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 19
- Humidity (%): 30 - 70
- Air changes (per hr): approximately 19
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5 mL destilled water

NEGATIVE CONTROL
No negative control was used.

POSITIVE CONTROL
No positive control was used.
Duration of treatment / exposure:
4 h
Observation period:
4 days
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm²
- Type of wrap if used: Each treatment site was occluded with elastic adhesive dressing.

REMOVAL OF TEST SUBSTANCE
- Washing: After exposure period, the treatment sides were washed using water.
- Time after start of exposure: 4 h

OBSERVATION TIME POINTS
Throughout the study, the rabbits were observed for clinical signs once daily. Examination of the treated skin and observations for erythema, eschar and oedema formation were performed on Day1 (approximately 30 min after removal of the patches) and on Days 2, 3 and 4.

SCORING SYSTEM:
- Method of calculation: According to OECD guideline 404, equivalent to the Draize scoring system.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
No erythema, eschar, oedema or other skin irritations were observed.
Other effects:
Clinical signs:
There were no clinical signs in any of the animals.
Interpretation of results:
other: According to the classification criteria of the CLP Regulation (EU) No. 1272/2008, no classification is required.
Conclusions:
The study is in accordance with EPA OPP 81-5 (Acute Dermal Irritation) and GLP. The skin irritation potential of the test substance was investigated following a 4 h exposure to New Zealand White rabbits. Under the conditions chosen, a single semi-occlusive application of the test substance to intact rabbit skin for 4 h elicited no dermal irritation. According to criteria of the CLP Regulation (EU) No. 1272/2008, no classification of the test item for skin irritation is required.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12 Mar - 13 Mar 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPP 81-4 (Acute Eye Irritation)
Version / remarks:
adopted in 1984
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
not specified
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: A. Smith, Surrey, UK
- Age at study initiation: approximately 12 weeks
- Weight at study initiation: 2.686 kg
- Housing: Animals were individually housed in metal cages with perforated floors.
- Diet: SDS standard rabbits diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: rabbit was acclimated to the laboratory environment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 19
- Humidity (%): 30 - 70
- Air changes (per hr): approximately 19
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 80 mg of the test substance accupying a volume of 0.1 mL
Duration of treatment / exposure:
single application without washing
Observation period (in vivo):
24 h
Number of animals or in vitro replicates:
1 (due to severity of effects)
Details on study design:
REMOVAL OF TEST SUBSTANCE
Test substance was not removed.

SCORING SYSTEM: Draize criteria as stated in OECD guideline 405

TOOL USED TO ASSESS SCORE: hand-slit lamp
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: The animal was sacrificed 24 h after instillation on humane grounds.
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: The animal was sacrificed 24 h after instillation on humane grounds. Necrosis and partial destruction of nictitating membrane was observed.
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24 h
Score:
2
Max. score:
2
Reversibility:
not reversible
Remarks on result:
other: The animal was sacrificed 24 h after instillation on humane grounds.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: The animal was sacrificed 24 h after instillation on humane grounds.
Irritant / corrosive response data:
An opacity covering the entire corneal surface was present 24 h after instillation. Iridial inflammation had developed by the 24-h reading. A diffuse beefy-red colouration of the conjunctivae accompanied by considerable swelling with the eyelids more than half-closed and a copious discharge were observed 24 h following instillation. Necrosis and partial destruction of the nictitating membrane were also present. Due to the severity of the response, only one animal was exposed to the test substance and the study was terminated due to animal welfare reasons 24 h after instillation.
Other effects:
There was no indication of a systemic effect of treatment.
Interpretation of results:
other: According to the classification criteria of the CLP Regulation (EU) No. 1272/2008, classification for eye damage Category 1 (H318) is warranted.
Conclusions:
The study is in accordance with EPA OPP 81-4 (Acute Eye Irritation) and GLP. The eye irritation potential of the test substance was investigated in New Zealand White rabbits by placing approximately 80 mg (0.1 mL) of the test substance into the lower everted lid of one eye. Under the conditions chosen, instillation of the test substance into the rabbit eye elicited a positive response. Severe eye damage was observed with eye irritation scores of 3, 2, 3 and 4 for cornea, iris, redness and chemosis, respectively. Due to the severity of the response, only one animal was exposed to the test substance and the study was terminated due to animal welfare reasons 24 h after instillation. According to the classification criteria of the CLP Regulation (EU) No. 1272/2008, classification for eye damage Category 1 (H318) is warranted.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Effects on skin irritation:

In a GLP-compliant study conducted according to EPA OPP 81-5 and similar to OECD 404, the test substance showed no skin irritating potential in the rabbit (Report number: 90500D/UCB 317/SE). No oedema or erythema was observed after exposure of 6 rabbits to 0.5 g of the test substance applied to intact skin and covered with a semi-occlusive for 4 h. This result was further supported by a skin irrtiation study conducted under GLP conditions and according to B.4 of Directive 92/69/EEC (Report number: 4397/T/220/94). The study is only mentioned here for purposes of data completeness. 3 rabbits were exposed to 0.5 g of the test substance using an occlusive patches for 4 h. Again, no erythema or oedema were observed.

In conclusion, the test substance did not exhibit skin irritating properties in the conducted studies. The available data on skin irritation of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.

Effects on eye irritation:

A GLP-conform eye irritation/corrosion study was performed according to EPA OPP 81-4 and similar to OECD 405 to evaluate the eye irritancy potential of the test substance (Report number: 90499D/UCB 318/SE). A single dose of 0.1 mL (equivalent to 80 mg) test substance was instilled to the eye of one rabbit and the eye was observed for 24 h. The test item showed severe irritant effects in the eye shown by a chemosis score of 4/4, conjunctivae score of 3/3, iris score of 2/2 and a cornea opacity score of 3/4 24 h after treatment. Necrosis and partial destruction of the nictitating membrane were also present. Due to the highly irritating effects observed, the study was determined after 24 h for animal welfare reasons. There were no indications of a systemic effect of the treatment with the test substance.

Severe eye irritating effects were also observed in a further study, which is only mentioned here for the purpose of data completeness (Report number: 4398/T/255/94). The study was conducted under GLP conditions and according to B.5 of Directive 92/69/EEC and OECD guideline 405. 0.1 mL (equivalent to 100 mg) of the test substance was instilled into the lower lid of one eye of 3 rabbits. Animals were examined 1 and 24 h after instillation. Due to the severity of effects and the response being regarded as causing unacceptable pain and distress to the animals, the study was terminated 24 h after the treatment. Eye damage was observed with mean eye irritation scores of 2, 1, 3 and 2.67 for cornea, iris, redness and chemosis, respectively 24 h after treatment. Further, necrosis of lower palpebral conjunctiva was observed.

In conclusion, the test substance did exhibit severe eye irritating properties in the conducted study. According to the classification criteria of the CLP Regulation (EU) No. 1272/2008, classification for eye damage Category 1 (H318) is warranted.

Effects on respiratory irritation:

Respiratory irritation was observed after single inhalation exposure of rats (Report number: UCB 314/89684 and 378/2). In detail, the test substance caused haemorrhaged and swollen lungs. Rats, which were sacrificed in extremis showed abnormally red, swollen and fluid filled lungs with dark patches. In addition, decreased or irregular respiratory rate was noted. For details on the respiratory effects after single inhalation exposure, please also refer to the respective study records and endpoint summary under acute toxicity. In addition to the respiratory effects observed after single inhalation exposure, the test substance also caused changes in the lungs after repeated-dose exposure via inhalation in rats (Report number: UCB 709/003932 and UCB 708/002245). Evidence of inflammatory, degenerative and proliferative changes were detected throughout the respiratory tract with increased lung weights and histopathological findings including e.g. fibrosis, granulomatous inflammation, bronchiolar metaplasia, prominent goblet, epithelial hyperplasia, bronchiolitis and an increased incidence of foamy alveolar macrophages and extravasation of eosinophils. In lungs, there was evidence of a degree of recovery. Therefore, the abovementioned animal studies provide evidence that the test substance cause respiratory tract irritation, which can be considered as reversible.

In conclusion, based on the available data on respiratory irritation of the test substance and according to the classification criteria of the CLP Regulation (EU) No. 1272/2008, classification for STOT-SE 3 (H335) is warranted.

Justification for classification or non-classification

The available data on skin irritation of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.

Based on the available data on eye and respiratory irritation and according to the classification criteria of the CLP Regulation (EU) No. 1272/2008, classification for eye damage Category 1 (H318) and STOT-SE 3 (H335) is warranted. This is in line with the harmonised classification of the test substance (Annex VI of Regulation (EC) 1272/2008, index number 066-012-00-2).